Skin Barrier Development Depends on CGI-58 Protein Expression during Late-Stage Keratinocyte Differentiation.

J. Invest. Dermatol.2017 Feb;137(2):403-413. Epub 2016 Oct 07

Susanne Grond ¹ , Franz P W Radner ¹ , Thomas O Eichmann ¹ , Dagmar Kolb ² , Gernot F Grabner ¹ ,

Susanne Grond ¹ , Franz P W Radner ¹ , Thomas O Eichmann ¹ , Dagmar Kolb ² , Gernot F Grabner ¹ , Heimo Wolinski ³ , Robert Gruber ⁴ , Peter Hofer ¹ , Christoph Heier ¹ , Silvia Schauer ⁵ , Thomas Rülicke ⁶ , Gerald Hoefler ⁷ , Matthias Schmuth ⁴ , Peter M Elias ⁸ , Achim Lass ¹ , Rudolf Zechner ¹ , Guenter Haemmerle ⁹

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¹ Institute of Molecular Biosciences, University of Graz, Graz, Austria.
² Center for Medical Research/Institute of Cell Biology, Histology and Embryology, Medical University of Graz, Graz, Austria.
³ Institute of Molecular Biosciences, University of Graz, Graz, Austria; BioTechMed-Graz, Microscopy Facility, University of Graz, Graz, Austria.
⁴ Department of Dermatology, Venereology and Allergology, University of Innsbruck, Innsbruck, Austria.
⁵ Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
⁶ Institute of Pathology, Medical University of Graz, Graz, Austria.
⁷ BioTechMed-Graz, Microscopy Facility, University of Graz, Graz, Austria; Institute of Pathology, Medical University of Graz, Graz, Austria; Institute of Laboratory Animal Science, University of Veterinary Medicine Vienna, Vienna, Austria.
⁸ Department of Dermatology, University of California San Francisco, San Francisco, California, USA.
⁹ Institute of Molecular Biosciences, University of Graz, Graz, Austria. Electronic address: guenter.haemmerle@uni-graz.at.

摘要

Adipose triglyceride lipase (ATGL) and its coactivator comparative gene identification-58 (CGI-58) are limiting in cellular triglyceride catabolism. Although ATGL deficiency is compatible with normal skin development, mice globally lacking CGI-58 die postnatally and exhibit a severe epidermal permeability barrier defect, which may originate from epidermal and/or peripheral changes in lipid and energy metabolism. Here, we show that epidermis-specific disruption of CGI-58 is sufficient to provoke a defect in the formation of a functional corneocyte lipid envelope linked to impaired Ï-O-acylceramide synthesis. As a result, epidermis-specific CGI-58-deficient mice show severe skin dysfunction, arguing for a tissue autonomous cause of disease development. Defective skin permeability barrier formation in global CGI-58-deficient mice could be reversed via transgenic restoration of CGI-58 expression in differentiated but not basal keratinocytes suggesting that CGI-58 is essential for lipid metabolism in suprabasal epidermal layers. The compatibility of ATGL deficiency with normal epidermal function indicated that CGI-58 may stimulate an epidermal triglyceride lipase beyond ATGL required for the adequate provision of fatty acids as a substrate for Ï-O-acylceramide synthesis. Pharmacological inhibition of ATGL enzyme activity similarly reduced triglyceride-hydrolytic activities in wild-type and CGI-58 overexpressing epidermis implicating that CGI-58 participates in Ï-O-acylceramide biogenesis independent of its role as a coactivator of epidermal triglyceride catabolism.

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